In vitro ALS model

Cambridge, Massachusetts -

Generation of in vitro models of human diseases allows utilization of high-throughput screening, as well as isolated molecular dissection of events in order to identify targets for intervention.

A recent paper (Di Giorgio et al. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model Nat Neurosci. 2007 Apr 15) developed an in vitro model of ALS using mouse ES cells that have been transgenically manipulated to express human wild-type or mutant SOD. The authors identified that coculture of transgenically modified neurons with glial cells expressing mutations in the SOD gene resulted in enhancement of neuron apoptosis.

These data support the notion that glial cells are involved in the pathogenesis of ALS. Utilization of glial cell modulating compounds may have therapeutic potential for drug development in the treatment of ALS. Since glial cells have similarities to macrophages, it is interesting to ask whether compounds used for modulating macrophage activity, such as thalidomide or pentoxyphillin have potential in treatment of ALS.

[Epub ahead of print].Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K.
¹ The Stowers Medical Institute, the Harvard Stem Cell Institute. Harvard University, 7 Divinity Ave., Cambridge, Massachusetts 02138, USA. [2] the Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Ave., Cambridge, Massachusetts 02138, USA. [3] Perugia Universita Piazza dell' Universita 1, Perugia 06100, Italy. [4] These authors contributed equally to this work.

Here we report an in vitro model system for studying the molecular and cellular mechanisms that underlie the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Embryonic stem cells (ESCs) derived from mice carrying normal or mutant transgenic alleles of the human SOD1 gene were used to generate motor neurons by in vitro differentiation. These motor neurons could be maintained in long-term coculture either with additional cells that arose during differentiation or with primary glial cells. Motor neurons carrying either the nonpathological human SOD1 transgene or the mutant SOD1 allele showed neurodegenerative properties when cocultured with SOD1 glial cells. Thus, our studies demonstrate that glial cells carrying a human SOD1 mutation have a direct, non-cell autonomous effect on motor neuron survival. More generally, our results show that ESC-based models of disease provide a powerful tool for studying the mechanisms of neural degeneration. These phenotypes displayed in culture could provide cell-based assays for the identification of new ALS drugs.